Aromatic substituted pyrazola {8 1,5a{9 {0 pyrimidine compounds useful as xanthine oxidase inhibitors

ABSTRACT

Compounds of the following structure are disclosed which are effective inhibitors of the enzyme xanthine oxidase:   R is an aromatic or substituted aromatic nucleus such as phenyl, R1 is H, an alkali metal or ammonium, and R2 is H or OR1.

United States Patent 1191 Springer et al.

[111 3,920,652 Nov. 18, 1975 1 AROMATIC SUBSTITUTED PYRAZOLA [1,5A] PYRIMIDINE COMPOUNDS USEFUL AS XANTHINE OXIDASE INHIBITORS [75] Inventors: Robert H. Springer, Santa Ana;

Darrell E. OBrien, Mission Viejo; Lionel N. Simon, Santa Ana, all of Calif.

[73] Assignee: ICN Pharmaceuticals, Inc., Irvine,

Calif.

[22] Filed: June 8, 1972 21 Appl. No.2 261,103

Related US. Application Data [63] Continuation-impart of Ser. No. 172,195, Aug. 16,

1971, abandoned.

[52] US. Cl. 260/256.4 F; 260/294.9; 260/296 R; 260/310 R; 260/340.5; 260/465 R; 260/465 D; 260/465 G; 424/251 OTHER PUBLICATIONS Dashkevich et al., CA. 77, 5401 f 1972), Abstract of Khim. Geterotsikl. Soedin., 1971, 7(8), 1145-1147.

Primary Examiner-Raymond V. Rush Attorney, Agent, or Firm-William E. Thomson; John F. OFlaherty; Kay l-I. Boswell [57] ABSTRACT Compounds of the following structure are disclosed which are effective inhibitors of the enzyme Xanthine oxidase:

R is an aromatic or substituted aromatic nucleus such as phenyl, R is H, an alkali metal or ammonium, and R is H or OR 15 Claims, No Drawings AROMATIC SUBSTITUTED PYRAZOLA [1,5A] PYRIMIDINE COMPOUNDS USEFUL AS XANTI-IINE OXIDASE INHIBITORS This application is a continuation-in-part of our copending application, Ser. No. 172,195, filed Aug. 16, 1971, entitled Xanthine Oxidase Inhibitors and now abandoned.

BACKGROUND OF THE INVENTION It is now well established that the enzyme xanthine oxidase is implicated in the production of uric acid by the body, converting hypoxanthine into xanthine and xanthine, in turn, into uric acid. Under normal conditions, uric acid (2,6,8-trioxypurine) is found in the body in only small amounts, a concentration in the blood on the order of about one to about three micrograms per 100 milliliters. Under certain pathological conditions, however, as for example, gout, the concentration of uric acid increases significantly.

Gout, of course, is a metabolic disturbance in the body resulting from an overproduction of uric acid, chronic hyperuricemia (elevated blood uric acid), and progressive accumulation of uric acid in the tissues. The body may also progressively lose its capacity to excrete uric acid and is, therefore, in a constant state of uric acid imbalance, accumulating a greater and greater excess. Its concentration in the blood is high, and, because of its low solubility, it tends to precipitate and form deposits at various sites where the blood flow is least active, particularly joints and cartilaginous tissues.

One approach to the control of gout commonly used in the past has been the prescription of drugs which tended to prevent the accumulation of uric acid in the body and thus diminish the likelihood of acute recurrences. Such drugs are identified as uricosuric agents and promote the excretion of uric acid in the urine. Examples of such drugs include p-dipropylsulfamyl benzoic acid and sulfinpyrazone. These drugs cannot, however, be administered in conjunction with aspirin or any other salicylate, which might be given to relieve pain, because the agents and salicylates are mutually antagonistic, i.e., each tends to offset the action of the other.

A second approach to the treatment of gout which has become popular is the use of the drug allopurinol,

KN i NH which blocks the production of uric acid by the body by inhibiting the enzyme xanthine oxidase, which, as noted previously, is responsible for converting hypoxanthine into xanthine and xanthine into uric acid. While allopurinol is effective to inhibit the enzyme xanthine oxidase, nevertheless there are disadvantages which limit its suitability.

First, its toxicity is higher than desirable, having a lethal dosage level, LD (the dose required to kill 50% of a group of animals in two weeks when injected into the intraparietal cavity) of about 150 milligrams per kilogram of body weight. Moreover, allopurinol is gradually metabolized in vivo to 4,6-dihydroxy pyrazolo [3,4-d] pyrimidine, which is not as effective an inhibitor as is allopurinol. In addition to the foregoing disadvantages, allopurinol, because of its chemical nature, must compete with xanthine to occupy a place on the enzyme xanthine oxidase in order to inhibit the enzyme and thus prevent the formation of uric acid by the body, which likewise limits its efficiency. It is also known that acute attacks of gouty arthritis occur in the early treatment with allopurinol. It is accordingly necessary to give colchicine during the initial period of therapy to prevent such acute attacks. There have also been reports of the development of a pruritic rash in some patients and of the occasional occurence of drowsiness when allopurinol is administered. In view of the foregoing, it is apparent that xanthine oxidase inhibitors which are of acceptable toxicity and at the same time possess increased inhibition efficiency as compared to allopurinol are highly desirable.

In the application of Darrell E. OBrien and Roland K. Robins entitled Xanthine Oxidase Inhibitors, Ser. No. 172,196, filed Aug. 16, 1971 and now abandoned, assigned to the same assignee as this application, imidazo [l,2,a] and pyrazolo[ l,5,a]pyrimidine compounds are disclosed which demonstrate significant inhibitory activity. Certain of such compounds possess greater inhibition against the enzyme xanthine oxidase than does allopurinol. While such compounds are thus effective inhibitors, there is yet the need for inhibitors possessing still increased efficiency.

SUMMARY OF THE INVENTION The present invention thus relates to xanthine oxidase inhibitors comprising pyrazolo[l,5a]pyrimidine compounds of the following general structure:

R is an aromatic or substituted aromatic nucleus, as for example, phenyl, naphthyl, tolyl, halogenated phenyls, heterocyclic nucleus, etc., R is H, an alkali metal or ammonium, and R is H or OR DETAILED DESCRIPTION OF THE INVENTION The xanthine oxidase inhibitors of this invention are represented by the foregoing structure. As will be seen from the illustrative examples which follow, such compounds demonstrate inhibitory activity significantly greater than allopurinol, in some cases on the order of to 200 times greater.

The R substituent, as indicated previously, is an aromatic or substituted aromatic nucleus. Examples of such substituents include phenyl, l-naphthyl, substituted phenyls of the formula there R is CH a halogen, or

3,920,652 3 4 O tate (malonaldehydic ester) in anhydrous ethanol affords the sodium salt of various 3-aryl-7-hydrox- NH c cl-l.,,

ypyrazolo[l,5a]pyrimidmes. When these sodium salts m-tolyl, heterocyclic nucleus as for example 5 'R, is preferably l-l thus yielding 5,7-dihydroxy pyrazoare dissolved in water and precipitated by the addition lo[l,5a] pyrimidines when R is CR although physioof hydrochloric acid, 3-aryl-7-hydroxypyrazolo [l,5a]- logically acceptable salts as for example, alkali metal or pyrimidines, represented by (V), are obtained. ammonium, may also be used.

The method of preparing the compounds of the present invention is described in detail in the examples which follow. In general, the synthesis method is as fol- 2O 2 06 A? h W/S lows. 2 5 I Following the general procedure of E. L. Anderson, l A/ J. E. Casey, Jr., L. C. Greene, J. J. Lafferty, and H. E. (7/

Reiff (J. Med. Chem, 1, 259 (1964)), 3-amino-4-aryl H pyrazoles (III) are prepared from aryl acetonitrile de- 25 H- {TO/Vw rivatives (l). I

Ar A

i r Ar Ar H N l l 2 I HO I l-lC CHO HN- N a c N C N Oil I ll I I I IV The condensation of such 3-amino-4-aryl pyrazoles An alternative procedure that is employed for the (III) with diethyl malonate in the presence of sodium preparation of these derivatives involves the condensaethoxide solution affords the disodium salts of 3-aryltion of the various 3-amino-4-arylpyrazoles (III) with 5,7-dihydroxypyrazolo [l,5a]pyrimidine. When these diethyl ethoxymethylene malonate in acetic acid solusodium salts are dissolved in water and treated with dition to afford various 3-aryl-6-carbethoxy-7-hydroxlute hydrochloric acid, 3-aryl-5,7-dihydroxypyrazolo[ l,5a]pyrimidines (VI). Refluxing a solution ypyrazolo[l,5a]pyrimidines, represented by (IV), are of these 3-aryl-6-carbethoxy-7-hydroxypyrazolo[1,5a]- obtained. It will, of course, be understood that aryl in pyrimidines (VI) in 40% sulfuric acid affords the correthe foregoing general reaction scheme represents the sponding 3-aryl-7-hydroxypyrazolo[ l,5a]pyrimidines various aromatic and substituted aromatic nuclei of the (V).

compounds of this invention.

u I Z 7 .ZZZ'+(|-(//-0! 2.. N My 5 2 i N ll 0 0 0/1 JZZ Similarly, the condensation of such 3-amino-4-aryl- The invention will be better understood by reference pyrazoles (III) with the sodium salt of ethyl -formylaceto the following specific but illustrative examples. Ul-

traviolet spectra were recorded on a Cary-l5 spectrophotometer.

EXAMPLE I Preparation of 3-phenyl pyrazolo[ l,5,a]pyrimidine-5,7-diol A solution of sodium ethoxide was prepared by dissolving sodium [l.7g (0.074 formula weights)] in 200 ml of absolute ethanol. Diethylmalonate [6.8g, 42.5

mmoles] and 3-amino-4-phenyl pyrazole [6.0g, 37.7

mmoles] were added to the sodium ethoxide solution. The resultant solution was stirred and heated at reflux temperature for 16 hours. The mixture wasthen allowed to cool to room temperature and the sodiumsalt of the product collected by filtration. The sodium salt was washed well with ethanol, air dried, and then dissolved in 150 ml of water. Acidification of this solution with 6N hydrochloric acid until a pH of- 1-2 was ob- EXAMPLE 11 Preparation of 3-(m-tolyl) pyrazolo[ 1,5 ,a]pyrimidine-S ,7-diol A solution of sodium ethoxide was prepared by dissolving sodium [l.6g (0.0695 formula weights)] in 200 ml of absolute ethanol. Diethylmalonate [6.2g, 38.7 mmoles] and 3-amino-4-(m-tolyl) pyrazole [6.0g, 34.7 mmoles]were added to the sodium ethoxide solution. The resultant solution was stirred and slowly warmed to reflux temperature. After reflux was obtained, the white sodium salt of the product began to precipitate. The reflux and stirring were continued for 16 hours and then the mixture was allowed to cool to room temperature. The sodium salt was separated by filtration, washed with absolute ethanol 3(200 ml) and air dried. The sodium salt was then dissolved in 300 ml of water, and the product precipitated from the solution by the addition of 6N hydrochloric acid until a pH of 1-2 was obtained. The product was thoroughly washed with water and dried at 100. Purification was accomplished by dissolving the product in dilute sodium hydroxide solution and reprecipitating with 6N hydrochloric acid. The product after purification weighed 2.93g (35%) and had a melting point of 284-5 (du); A max (pHl) 207 nm (29,200) and 240 nm (a 20,500); A max (pHl 1) 230 nm (26,400) and 286 nm (6 18,800).

Anal. calcd. for C H N O C, 64.8; H, 4.57; N, 17.4. Found: C, 64.9; H, 4.66; N, 17.4.

EXAMPLE lII Preparation of 3-(p-tolyl)pyrazolo[ 1 ,5,a]pyrimidine-5,7-diol A solution of sodium ethoxide was prepared by dissolving sodium [2.13g (0.092 formula weights)] in 200 ml of absolute ethanol. Diethylmalonate [8.2g, 51 mmoles] and 3-amino-4-(p-tolyl)pyrazole[8.0g, 46.2 mmoles] were added to the sodium ethoxide solution.

The resultant solution was stirred and slowly warmed to reflux temperature. After reflux was obtained, the white sodium salt of the product began to precipitate.

The reflux and stirring were continued for 6 hours and then the mixture was allowed to cool to room temperature. -The sodium salt was separated by filtration,

washed with absolute ethanol, air dried, and then dissolved in 300 ml of water. Acidification of this solution with 6N hydrochloric acid until a pH of 1-2 was obtained afforded the product. The product was separated by filtration, washed with water, dried at and purified by reprecipitating from sodium hydroxide solution by the addition of 6N hydrochloric acid. The product after purification weighed 4.55g (41%) and had a melting point of 2557 (dec); A max (pHl) 203 nm (e 30,600) and 243 nm (6 20,500).

Anal. calcd. for C H N O C, 64.8; H, 4.57; N, 17.4. Found: C, 64.9; H, 4.51; N, 17.3.

EXAMPLE IV Preparation of 3-(p-bromophenyl )pyrazolo[ 1,5 ,a]pyrimidine-S ,7-diol A solution of sodium ethoxide was prepared by dissolving sodium [0.97g (0.042 formula weights)] in 100 ml of absolute ethanol. Diethylmalonate [.7g, 23 mmoles] and 3-amino-4-(p-bromophenyl)- pyrazole[5.0g, 21 mmoles] were added to the sodium ethoxide solution. The resultant solution was stirred and slowly warmed to reflux temperature. After reflux was obtained, the white sodium salt of the product began to precipitate from the solution. The reflux and stirring were continued for 6 hours, and then the mixture was allowed to cool to room temperature. The sodium salt was separated by filtration, washed with absolute ethanol, air dried, and dissolved in 100 ml of water. The product was precipitated from this solution by the addition of 6N hydrochloric acid until a pH of 1-2 was obtained. The product was separated by filtration, washed with water, dried at 100, and purified by reprecipitating from sodium hydroxide solution by the addition of 6N hydrochloric acid. The product after purification weighed 2.31g (36 and had a melting point of 330 (dec); X max (pHl) 202 nm (6 31,900) and 247 nm (6 27,500); A max (pHl l) 234 nm (6 41,400) and 308 nm (6 37,100).

Anal. Calcd. for C H BrN O C, 47.1; H, 2.62; N, 13.7. Found: C, 47.2; H, 2.58; N, 13.8.

EXAMPLE v Preparation of 3-(p-chlorophenyl) pyrazolo[ l ,5 ,a]pyrimidine-S ,7-diol A solution of sodium ethoxide was prepared by dissolving sodium [0.356g (0.0155 formula weights)] in 100 ml of absolute ethanol. Diethylmalonate [1.38g, 8.6 mmoles] were added to the sodium ethoxide solution.- The resultant solution was stirred and slowly warmed to reflux temperature. After reflux was obtained, the white sodium salt of the product began to precipitate from the solution. The reflux and stirring were continued for 6 hours, and then the mixture was allowed to cool to room temperature. The sodium salt was separated by filtration, washed with absolute ethanol, air dried, and dissolved in 100 ml of water. The product was precipitated from this solution by the addition of 6N hydrochloric acid until a pH of l-2 was obtained. The product was separated by filtration, washed with water, dried at 100, and purified by reprecipitating from sodium hydroxide solution by the addition of 6N hydrochloric acid. The product after purification weighed 1.16g (57%) and had a melting point of 3301(dec); Amax (pHl 204 nm (e 26,500) and 245 nm (6 23,700); A max (pHll) 233 nm (6 24,000) and 305 nm (6 21,500).

Anal. calcd. for C H ClN O C, 55.1; H, 3.06; N, 16.1. Found: C, 55.1; H, 3.06; N, 16.2.

EXAMPLE VI Preparation of 3-( p-acetamidophenyl )pyrazolo[ l ,5,a]pyrimidine-5,7- diol A solution of sodium ethoxide was prepared by dissolving sodium [l.06g (0.046 formula weights)] in 200 ml of absolute ethanol. Diethylmalonate [4.2g, 26 mmoles] were added to the sodium ethoxide solution. The resultant solution was stirred and heated at reflux temperature for 16 hours. The mixture was then allowed to cool to room temperature and the sodium salt of the product collected by filtration. The sodium salt was washed well with ethanol, air dried, and then dissolved in 150 ml of water. Acidification of this solution with 6N hydrochloric acid until a pH of 12 was obtained afforded the product. The product was separated by filtration, washed with water, and dried at 100. Reprecipitation of this product from dilute sodium hydroxide solution by the addition of 6N hydrochloric acid afforded 3.54g (54%) of analytically pure product; 2724 (dec); A max (pHl) 204 nm (6 38,500) and 262 nm (6 31,100); A max (pHll) 232 nm (6 36,000) and 311 nm (32,000).

Anal. calcd. for C H N O 2H O; C, 52.4; H, 5.03; N, 17.5. Found: C, 52.5; H, 5.10; N, 17.8.

EXAMPLE VII Preparation of 3-piperonylpyrazolo[ 1,5,a]pyrimidine-5,7-diol A solution of sodium ethoxide was prepared by dissolving sodium [1.78g (0.077 formula weightsO] in 200 ml of absolute ethanol. Diethylmalonate [3.21g, 20 mmoles] and 3-amino-4-piperonylpyrazole[3.65g, 17.9 mmoles] were added to the sodium ethoxide solution. The resultant solution was stirred and heated at reflux temperature for 16 hours. The mixture was then allowed to cool to room temperature and the sodium salt was washed well with ethanol, air dried, and then dissolved in 150 ml of water. Acidification of this solution with 6N hydrochloric acid until a pH of 1-2 was obtained afforded the product. The product was separated by filtration, washed with water, and dried at 100. Reprecipitation of this product from dilute sodium hydroxide solution by the addition of 6N hydrochloric acid afforded 3.25 g (59%) of analytically pure product; 2456 (dec); A max (pHl) 305 nm (e 29,950), 257 nm (sh) (6 13,300) and 295 nm (e 10,450), Amax(pH11) 230 nm (6 17,300) and 275 nm (6 14,100).

Anal. calcd. for C H N O C, 57.6; N, 3.34; N, 15.5. Found: C, 57.3; H, 3.62; N, 15.5.

EXAMPLE VIII Preparation of 3-( 3 '-pyridyl)pyrazolo[ 1,5,a]pyrimidine-5,7-diol A solution of sodium ethoxide was prepared by dissolving sodium [2.76g (0.12 formula weights)] in 200 tion. The resultant solution was stirred and slowly warmed to reflux temperature. After reflux was obtained, the sodium salt of the product began to precipitate. The reflux and stirring were continued for 16 hours and then the mixture was allowed to cool to room temperature. The sodium salt was separated by filtration, washed with absolute ethanol 3(200 ml) and air dried. The sodium salt was then dissolved in 300 ml of water, and the product precipitated from the solution by the addition of 6N hydrochloric acid until a pH of 1-2 was obtained. The product was separated by filtration, washed with water, and dried at Purification was accomplished by dissolving the product in dilute EXAMPLE IX Preparation of 3-( 1 -naphthyl)pyrazolo[ 1,5,a]pyrimidine-5,7-diol A solution of sodium ethoxide was prepared by dissolving sodium [1.38g (0.06 formula weights 0] in 200 ml of absolute ethanol. Diethylmalonate [5.27g, 33 mmoles] and 3-amino-4-( l '-naphthyl)pyrazole[6.26g, 30 mmoles] were added to the sodium ethoxide solution. The resultant solution was stirred and heated at reflux temperature for 16 hours. The mixture was then allowed to cool to room temperature and the sodium salt of the product collected by filtration. The sodium salt was washed well with ethanol, air dried, and then dissolved in ml of water. Acidification of this solution with 6N hydrochloric acid until a pH of 1-2 was obtained afforded the product. The product was separated by filtration, washed with water and dried at 100. Reprecipitation of this product from dilute sodium hydroxide solution by the addition of 6N hydrochloric acid afforded 1.91g (23%) of analytically pure product; 2l9-21 (dec); A max (pH 1) 205 nm (6 32,500) 256 nm (6 15,700) and 290 nm (6 12,100); A max (pHl 1) 230 nm (6 19,400) and 275 nm (6 15,700).

Anal. calcd. for C H N O- C, 69.3; H, 4.00; N, 15.2. Found: C, 68.5, H, 3.72 N, 14.9.

EXAMPLE x Preparation of 3-(m-tolyl)pyrazolo[ 1 ,5a]pyrimidin-7-ol A suspension of sodium metal [4.0 g, 0.174 formula weights] in absolute ether (1 liter) was stirred at room temperature while a mixture of ethyl formate [14.8 g, 0.2 moles] and ethyl acetate [17 g, 0.193 moles] was added dropwise. The resultant mixture was stirred at room temperature for 48 hours, at which time all of the sodium metal had reacted. The mixture was evaporated to dryness at reduced pressure and the residue of crude ethyla-formylacetate was dissolved in absolute ethanol (500 ml). This solution was stirred at room temperature while 3-amino-4-(m-tolyl)pyrazole [10.0 g, 0.0625 moles] was added. This mixture was then heated at reflux for 4 hours and then evaporated to dryness. The solid residue was dissolved in 200 ml of water, treated with decolorizing carbon, and filtered. Acidification of the filtrate with concentrated hydrochloric acid afforded 8.3 g (59%) of 3-(m-tolyl)pyrazolo[1,5a]- pyrimidin-7-ol that had a melting point of 308-10 (dec).

Reprecipitation of this product from dilute sodium hydroxide solution did not change the melting point. Max (pH 1) at 206 nm (6 24,600) and 272 nm (5, 13,080). A Max (pH 11) at 226 nm (6, 9,700) and 327 nm (e, 12,870); shoulder in pH 11 at 293 nm.

Anal. Calcd for C H N O; C, 69.5; H, 4.90; N, 18.7. Found: C, 69.5; H, 5.09; N, 18.5.

EXAMPLE XI Preparation of 3-(m-phenyl)pyrazolo[1,5a]pyrimidin-7-ol A suspension of sodium metal [4.0 g, 0.174 formula weights] in absolute ether (1 liter) was stirred at room temperature while a mixture of ethyl forrnate [14.8 g, 0.2 moles] and ethyl acetate [17 g, 0.193 moles] was added dropwise. The resultant mixture was stirred at room temperature for 48 hours, at which time all of the sodium metal had reacted. The mixture was evaporated to dryness at reduced pressure and the residue of crude ethyl a-formylacetate was dissolved in absolute ethanol (500 ml). This solution was stirred at room temperature while 3-amino-4-phenylpyrazole [10.0 g, 0.063 moles] was used. This mixture was then heated at reflux for 4 hours and then evaporated to dryness. The solid residue was dissolved in 200 ml of water, treated with decolorizing carbon, and filtered. Acidification of the filtrate with concentrated hydrochloric acid afforded 9.6 g (69%) of 3-phenylpyrazolo[1,5a]pyrimidine-7-ol that had a melting point of 3224 (dec). A Max (pH 1) at 208 nm (6, 26,800) and 273 nm (X, 12,150). e Max (pH 11) at 225 nm (6, 11,000) and 329 nm (6, 7,400); shoulder in pH 11 at 294 nm.

Anal. Calcd for C H N O: C, 68.3, H, 4.26, N, 19.9. Found: C, 68.1, H, 4.25, N, 20.2

EXAMPLE XII Preparation of 6-carbethoxy-3-(m-tolyl)pyrazolo[ 1 ,5a]pyrimidin-7- A solution of 3-amino-4-m-tolylpyrazole [18.3 g, 0.1 mole] and diethyl ethoxymethylenemalonate [21.6 g. 0.1 mole] in 200 ml of acetic acid was stirred and heated at reflux for 3 hours. A complete solution was formed initially; however, after refluxing for about 1% hours the product began to precipitate from the boiling solution. The mixture was allowed to cool to room temperature, and the product was separated by filtration, washed with methanol, and dried. Recrystallization from a mixture of dimethylformamide and water afforded 18.6 g (63%) of analytically pure 6-carbethoxy 3-(m-tolyl)pyrazolo[1,5a] pyrimidin-7-ol that had a 1 10 (6, 32,700) and 292 nm (6, 13,660). A Max (pH 11) 227 nm (6, 17,800) and 319 nm (e, 22,300).

Anal. calcd for C H N O C, 64.6; H, 5.05; N, 14.12. Found: C, 64.53; H, 5.09; N, 14.11.

EXAMPLE XIII Preparation of 3-( m-tolyl)pyrazolo[ 1 ,5a]pyrimidin-7-ol.

A suspension of 6-carbethoxy-3-(m-tolyl)pyrazolo [1,5a]pyrimidin-7-ol (1 g] in 5 ml of 40% sulfuric acid was stirred and heated at reflux for 2% hours. At the end of this time, the solution was cooled and added to 10 ml of water. Aqueous sodium hydroxide solution was added to this suspension until a pH of 4 was obtained. The white product was separated by filtration, washed with water, and then recrystallized from a mixture of dimethylformamide and water to afford analytically pure 3-(m-tolyl)pyrazolo[1,5a] pyrimidin-7-ol that is identical in all respects to the product obtained in Example X.

EXAMPLE XIV In this example, the inhibitory activity of the compounds of the invention was determined by recording spectral changes at a constant wavelength of 290 nm, using a Cary Model 15 recording spectrophotometer equipped with a 00.1 O.D. slidewire. To facilitate dissolution in the incubation mixture, the compounds of this invention were dissolved in DMSO (pure spectral grade), which is a good solvent and also one which does not inhibit the enzyme. After dissolving in DMSO, the compounds were introduced into the incubation mixture containing 150 micromoles of tris HCl buffer (pH 7.50), 0.6 micromoles EDTA, 0.013 micromoles xanthine, and 20 to 40 micrograms of xanthine oxidase in a final volume of 3.0 milliliters. The xanthine oxidase was purified milk xanthine oxidase from Worthington Biochemical Corporation and had a specific activity of 0.29 u/mg of protein. The assay was carried out by mixing all the components in a cuvette at 25 C. The reaction was started by the addition of the enzyme with the aid of a stirrer-adder. Changes in OD. were measured for several minutes, and the rate (AO.D. per minute) was calculated from the spectral change over the first 15 seconds.

In order to fully evaluate the inhibitory activity and to compare the relative inhibitory abilities of the compounds of this invention with allopurinol, experiments were carried out in which the concentration of inhibitor was varied over a range of approximately 10 to about 10 molar and the initial velocity of xanthine oxidation was measured. From a plot of the log of inhibitor concentration against the percent inhibition, the concentration of inhibitor giving 50% inhibition (I was calculated. This value was obtained from a linear regression analysis of the straight lines obtained in this graph. The data is presented in Table I as (1 values, and relative activity (a) of the particular compounds of the invention compared to allopurinol is also presmelting point of 278-80 (dec). A Max (pH 1) 211 nm ented Table I Compound 15., Allopurinol R R R2 a I50 Compound H OH 9.6 x 10- 52 Table l-continued Compound I Allopurinol I Compound H OH 4.3 X H6 T1 NHCCH3 H 0H 8.9 X 10- 56 CH 3 H 0H 2.5 10- 2011 (Di; H 0H 2.9 x 10-" 172 o\ H 0H 4.3 1o- 116 ()1 H OH 2.5 X 10 H H 1.0 x 10- 7 Allopurinol 5 X 10 1 It will be appreciated from the foregoing data that all times greater than allopurinol. It should also be noted of the compounds of this invention demonstrated activthat the compounds of the present invention also posity at least twenty times greater than the commercial sess acceptable toxicity levels, LD generally on the product, allopurinol. Indeed, Compounds 2, 3, 5, 6, 7 order of approximately 200 milligrams per kilogram of and 8 exhibited activity ranging between and 200 body weight.

The xanthine oxidase inhibitors are administered as oral preparations, in capsule or tablet form. The tablets or capsules will contain from about 0.5 to about 50 milligrams of the inhibitor per tablet or capsule. The required dose of the inhibitor, of course, will vary depending upon the condition of the patient, but will normally range from approximately to 200 milligrams per day. To inhibit effectively the enzyme xanthine oxidase, a concentration in the blood of approximately 1 to about 500 micrograms of the inhibitor per milliliter is required, preferably from 1 to about 50 micrograms per milliliter.

We claim: 1. A compound of the formula wherein R is phenyl, m-methylphenyl, p-methylphenyl, p-halophenyl, p-acetamidophenyl, 3,4-methylenedioxyphenyl, a-naphthyl or 3-pyridyl; R is H, alkali metal or ammonium; and R is H or OR,.

2. The compound of claim 1 in which R is phenyl. 3. The compound of claim 1 in which R is in which R is methyl, a halogen, or

4. The compound of claim 1 in which R is 5. The compound of claim 1 in which R is 6. The compound of claim 1 in which R is 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 in which R is phenyl.
 3. The compound of claim 1 in which R is
 4. The compound of claim 1 in which R is
 5. The compound of claim 1 in which R is
 6. The compound of claim 1 in which R is
 7. The compound of claim 3 in which R3 is Cl.
 8. The compound of claim 3 in which R3 is Br.
 9. 3-phenylpyrazolo(1,5a)pyrimidine-5,7-diol.
 10. 3-(m-tolyl)pyrazolo(1,5a)pyrimidine-5,7-diol.
 11. 3-(p-bromophenyl)pyrazolo(1,5a)pyrimidine-5,7-diol.
 12. 3-piperonylpyrazolo(1,5a)pyrimidine-5,7-diol.
 13. 3-(m-tolyl)pyrazolo(1,5a)pyrimidine-7-ol.
 14. 3-phenylpyrazolo(1,5a)pyrimidine-7-ol.
 15. 3-(3''-pyridyl) pyrazolo (1,5a) pyrimidine-5,7-diol 